Pancreatic ductal adenocarcinoma (PDA) is virtually a lethal disease for which no gold-standard detection method exists and virtually no significant treatment improvements have occurred within the last 30 years. Because PDA is associated with metastases at presentation, hypovascularity, desmoplasia, acidosis, overcoming the physical and microenvironmental barriers to deliver efficacious drugs to pancreatic tumor cells remains elusive. In this endeavor, we have developed an ultra-acidic pH-responsive theranostic (UPRT) nanoparticle, whose distribution within mice bearing orthotopic pancreatic tumors can also be quantitatively imaged by Optoacoustic Tomography, enabling whole body, real-time mapping of biodistribution and accumulation. Three innovative aspects in this proposal are: 1) development and characterization of UPRT polymeric drug carriers with a tunable and sharp pH response pH < 0.3 containing both a contrast agent and drug; 2) use of newly-emerging imaging technology, Multispectral Optoacoustic Tomography, for sensitive and specific detection of UPRT nanoparticles with quantitative assessment and innovative image analysis; 3) identification of pharmacokinetic/pharmacodynamics properties of the nanoparticle along with validation of Multispectral Optoacoustic Tomography imaging assays of UPRT nanoparticle delivery using standard methods, i.e. histology and LC-MS. Our overarching hypothesis is that UPRT-nanoparticles will target the acidic pH resulting from excessive lactic acid production associated with hypovascularity in pancreas tumors to deliver drugs to tumor cells and serve as a diagnostic contrast agent in vivo. Because Multispectral Optoacoustic Tomography (MSOT) has high sensitivity, high spatial resolution, increased depth of penetration, potential for whole-body imaging, and potential for longitudinal imaging, MSOT will be utilized to determine biodistribution and pharmacokinetic/pharmacodynamic properties of the proposed polymer-based, theranostic nanoparticles. To test this hypothesis, we will evaluate the following aims: 1) Characterize the biophysical properties, drug/contrast agent loading and release, and in vitro efficacy of UPRT nanoparticle; 2) Optimize design and kinetics of UPRT nanoparticle that delivers NIR dye/drugs to hypovascular tumor areas; 3) Determine spatiotemporal distribution, therapeutic efficacy, and toxicity profiles of UPRT nanoparticle using Multispectral Optoacoustic Tomography in orthotopic models of pancreatic adenocarcinoma which spontaneously metastasize. Detection and treatment of pancreatic cancer with this delivery system will likely constitute an effective approach to improve detection and drug delivery for these currently untreatable patients.